Significant variation in histopathological assessment of endoscopic resections for Barrett's neoplasia suggests need for consensus reporting: propositions for improvement.

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett's esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria.

The Amsterdam ReBus progressor cohort: identification of 165 Barrett's surveillance patients who progressed to early neoplasia and 723 nonprogressor patients.

Patient selection is suboptimal in most studies focused on identifying biological markers for neoplastic progression in Barrett's esophagus (BE). This study aims to describe a stringently selected community-based case-control cohort of non-dysplastic BE (NDBE) patients who progressed to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and BE patients who never progressed to be used for future biomarker studies. We identified all patients referred for endoscopic work-up of BE neoplasia at three tertiary referral centers for treatment of BE neoplasia between 2000 and 2013. We performed a detailed registration of any endoscopic surveillance history before neoplastic progression. Controls were selected from a retrospective BE surveillance registration in 10 community hospitals. A total of 887 patients were referred for endoscopic work-up of BE neoplasia. Based on predefined selection criteria, we identified 165 progressor patients (82% men; mean age 55 years ± 10.4) with a baseline endoscopy demonstrating NDBE > 2 years before neoplastic progression. Using the same predefined selection criteria, 723 nonprogressor patients (67% men; mean age 57 years ± 11.3) with >2 years of endoscopic surveillance were identified. Median length of the BE segment was 5 cm (IQR 4-7) in progressors and 4 cm (IQR 2-6) in controls. Median duration of surveillance was 89 months (IQR 54-139) in progressors and 76 months (IQR 47-116) in nonprogressors. Paraffin embedded biopsies are available for biomarker research in all patients. Ethical approval was obtained and material transfer agreements were signed with all 58 contributing pathology labs. This is the largest community-based case-control cohort of BE patients with and without progression to early neoplasia. The stringent selection criteria and the availability of paraffin embedded biopsy specimens make this a unique cohort for biomarker studies.

Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score.

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic .91) and reduced transplant-free survival (C-statistic .83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were .70 (0.59-0.81), .82 (0.75-0.89), .73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic .87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement.

Polypoid arteriovenous malformation of the ureter mimicking a fibroepithelial polyp, a case report.

BACKGROUND: Arteriovenous malformations (AVM) of the urinary tract are extremely rare. To the best of our knowledge, only three case of AVM of the ureter have been described in the literature so far. CASE PRESENTATION: We present an additional, fourth case of an AVM of the ureter, clinically presented as asymptomatic haematuria and an obstructive process in the left ureter. Ureteroscopic evaluation revealed a fibroepithelial polypoid-like lesion in the proximal ureter. After biopsy showed a benign lesion, the lesion was treated with the 2-µm continuous wave (cw) thulium laser. Histopathological examination revealed a polypoid laesion caused by a circumscribed arteriovenous malformation. Almost four years after operation the patient remains asymptomatic and free of recurrence. CONCLUSION: Arteriovenous malformations of the urinary tract are extremely rare. We presented a fourth case of a arteriovenous malformation of the ureter.

Preoperative chemoradiotherapy for esophageal or junctional cancer.

BACKGROUND: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Oncologic Long-Term Results of Robot-Assisted Minimally Invasive Thoraco-Laparoscopic Esophagectomy with Two-Field Lymphadenectomy for Esophageal Cancer.

BACKGROUND: Open transthoracic esophagectomy is the worldwide gold standard in the treatment of resectable esophageal cancer. Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) for esophageal cancer may be associated with reduced blood loss, shorter intensive care unit (ICU) stay, and less cardiopulmonary morbidity; however, long-term oncologic results have not been reported to date. METHODS: Between June 2007 and September 2011, a total of 108 patients with potentially resectable esophageal cancer underwent RAMIE at the University Medical Centre Utrecht, with curative intent. All data were recorded prospectively. RESULTS: Median duration of the surgical procedure was 381 min (range 264-636). Pulmonary complications were most common and were observed in 36 patients (33 %). Median ICU stay was 1 day, and median overall postoperative hospital stay was 16 days. In-hospital mortality was 5 %. The majority of patients (78 %) presented with T3 and T4 disease, and 68 % of patients had nodal-positive disease (cN1-3). In 65 % of patients, neoadjuvant treatment (chemotherapy 57 %, chemoradiotherapy 7 %, radiotherapy 1 %) was administered, and in 103 (95 %) patients, a radical resection (R0) was achieved. The median number of lymph nodes was 26, median follow-up was 58 months, 5-year overall survival was 42 %, median disease-free survival was 21 months, and median overall survival was 29 months. Tumor recurrence occurred in 51 patients and was locoregional only in 6 (6 %) patients, systemic only in 31 (30 %) patients, and combined in 14 (14 %) patients. CONCLUSION: RAMIE was shown to be oncologically effective, with a high percentage of R0 radical resections and adequate lymphadenectomy. RAMIE provided good local control with a low percentage of local recurrence at long-term follow up.

The significance of the HER-2 status in esophageal adenocarcinoma for survival: an immunohistochemical and an in situ hybridization study.

BACKGROUND: In esophageal adenocarcinoma (EAC), concordance and prognostic significance of human epidermal growth factor 2 (HER-2) protein overexpression and gene amplification are equivocal, which led us to reevaluate this by immunohistochemistry (IHC) and in situ hybridization. METHODS: One hundred and fifty-four patients were included in a tissue micro array (TMA). HER-2 gene amplification was assessed by fluorescence and silver-enhanced in situ hybridization (FISH and SISH) and expression with the HercepTest™. RESULTS: HER-2 was amplified in 16% by SISH and 18% by FISH. HER-2 positivity (IHC 3+ or 2+ with ISH+) was seen in 12% and overexpression (IHC 2+/3+) in 14%. Concordance was 92% between SISH/IHC, 90% between FISH/IHC and 95% between SISH/FISH. All IHC 3+ cases were amplified by SISH and in 93% by FISH. Of the IHC 2+cases, this was 33% (SISH) and 50% (FISH). Of the IHC 1+ cases, still 6% (SISH) and 8% (FISH) showed amplification. HER-2 positivity, overexpression and amplification were all associated with poor cancer-specific survival, in univariate analysis. Furthermore, HER-2 positivity and amplification (SISH) were independently associated with poor survival (hazard ratio, HR 6.343; 95% CI 1.218-36.234; P = 0.029 and HR 3.231; 95% CI 1.092-9.563; P = 0.034). CONCLUSION: HER-2 positivity and gene amplification are fairly frequent and independently associated with poor survival.

Hepatic regeneration and functional recovery following partial liver resection in an experimental model of hepatic steatosis treated with omega-3 fatty acids.

BACKGROUND: Omega-3 fatty acids (FAs) have been shown to reduce experimental hepatic steatosis and protect the liver from ischaemia-reperfusion injury. The aim of this study was to examine the effects of omega-3 FAs on regeneration of steatotic liver. METHODS: Steatosis was induced in rats by a 3-week methionine/choline-deficient diet, which was continued for an additional 2 weeks in conjunction with oral administration of omega-3 FAs or saline solution. Steatosis was graded histologically and quantified by proton magnetic resonance spectroscopy ((1) H-MRS) before and after the diet/treatment. Liver function was determined by (99m) Tc-labelled mebrofenin hepatobiliary scintigraphy (HBS). In separate experiments, the hepatic regenerative capacity and functional recovery of omega-3 FA-treated, saline-treated or non-steatotic (control) rats were investigated 1, 2, 3 and 5 days after partial (70 per cent) liver resection by measurement of liver weight change and hepatocyte proliferation (Ki-67) and HBS. RESULTS: Severe steatosis (over 66 per cent) in the saline group was reduced by omega-3 FAs to mild steatosis (less than 33 per cent), and hepatic fat content as assessed by (1) H-MRS decreased 2·2-fold. (99m) Tc-mebrofenin uptake in the saline group was more than 50 per cent lower than in the control group, confirming the functional effects of steatosis. (99m) Tc-mebrofenin uptake and regenerated liver mass were significantly greater in the omega-3 group compared with the saline group on days 1 and 3. The posthepatectomy proliferation peak response was delayed until day 2 in saline-treated rats, compared with day 1 in the omega-3 and control groups. CONCLUSION: Omega-3 FAs effectively reduced severe hepatic steatosis, which was associated with improved liver regeneration and functional recovery following partial hepatectomy.

Predictive factors for initial treatment response after circumferential radiofrequency ablation for Barrett's esophagus with early neoplasia: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Radiofrequency ablation (RFA) is safe and effective for the eradication of neoplastic Barrett's esophagus; however, occasionally there is minimal regression after initial circumferential balloon-based RFA (c-RFA). This study aimed to identify predictive factors for a poor response 3 months after c-RFA, and to relate the percentage regression at 3 months to the final treatment outcome. METHODS: We included consecutive patients from 14 centers who underwent c-RFA for high grade dysplasia at worst. Patient and treatment characteristics were registered prospectively. "Poor initial response" was defined as < 50 % regression of the Barrett's esophagus 3 months after c-RFA, graded by two expert endoscopists using endoscopic images. Predictors of initial response were identified through logistic regression analysis. RESULTS: There were 278 patients included (median Barrett's segment C4M6). In poor initial responders (n = 36; 13 %), complete response for neoplasia (CR-neoplasia) was ultimately achieved in 86 % (vs. 98 % in good responders; P < 0.01) and complete response for intestinal metaplasia (CR-IM) in 66 % (vs. 95 %; P < 0.01). Poor responders required 13 months treatment (vs. 7 months; P < 0.01) for a median of four RFA sessions (vs. three; P < 0.01). We identified four independent baseline predictors of poor response: active reflux esophagitis (odds ratio [OR] 37.4; 95 % confidence interval [CI] 3.2 - 433.2); endoscopic resection scar regeneration with Barrett's epithelium (OR 4.7; 95 %CI 1.1 - 20.0); esophageal narrowing pre-RFA (OR 3.9; 95 %CI 1.0 - 15.1); and years of neoplasia pre-RFA (OR 1.2; 95 %CI 1.0 - 1.4). CONCLUSIONS: Patients with a poor initial response to c-RFA have a lower ultimate success rate for CR-neoplasia/CR-IM, require more treatment sessions, and a longer treatment period. A poor initial response to c-RFA occurs more frequently in patients who regenerate their endoscopic resection scar with Barrett's epithelium, and those with ongoing reflux esophagitis, neoplasia in Barrett's esophagus for a longer time, or a narrow esophagus.

Focal nodular hyperplasia: hepatobiliary enhancement patterns on gadoxetic-acid contrast-enhanced MRI.

OBJECTIVES: To assess the range of hepatobiliary enhancement patterns of focal nodular hyperplasia (FNH) after gadoxetic-acid injection, and to correlate these patterns to specific histological features. MATERIALS AND METHODS: FNH lesions, imaged with Gadoxetic-acid-enhanced MRI, with either typical imaging findings on T1, T2 and dynamic-enhanced sequences or histologically proven, were evaluated for hepatobiliary enhancement patterns and categorized as homogeneously hyperintense, inhomogeneously hyperintense, iso-intense, or hypo-intense-with-ring. Available histological specimens of FNHs (surgical resection or histological biopsy), were re-evaluated to correlate histological features with observed enhancement patterns. RESULTS: 26 FNHs in 20 patients were included; histology was available in six lesions (four resections, two biopsies). The following distribution of enhancement patterns was observed: 10/26 homogeneously hyperintense, 4/26 inhomogeneously hyperintense, 5/26 iso-intense, 6/26 hypointense-with-ring, and 1/26 hypointense, but without enhancing ring. The following histological features associated with gadoxetic-acid uptake were identified: number and type of bile-ducts (pre-existent bile-ducts, proliferation, and metaplasia), extent of fibrosis, the presence of inflammation and extent of vascular proliferation. CONCLUSION: FNH lesions can be categorized into different hepatobiliary enhancement patterns on Gadoxetic-acid-enhanced MRI, which appear to be associated with histological differences in number and type of bile-ducts, and varying the presence of fibrous tissue, inflammation, and vascularization.

Radiofrequency ablation and endoscopic resection in a single session for Barrett's esophagus containing early neoplasia: a feasibility study.

BACKGROUND AND STUDY AIM: Endoscopic resection with radiofrequency ablation (RFA) 6 weeks later safely and effectively eradicates Barrett's esophagus with high grade dysplasia (HGD) and early cancer. After widespread endoscopic resection, related scarring may hamper balloon-based circumferential RFA (c-RFA). However c-RFA immediately followed by endoscopic resection in the same session might avoid the impact of scarring and reduce laceration and stenosis risk. We aimed to assess the feasibility of such an approach. PATIENTS AND METHODS: Patients with Barrett's esophagus ≥ 3 cm and ≥ 1 visible lesion (HGD/early cancer) were included. Visible lesions were marked with cautery, and c-RFA (12 J/cm2) was delivered using two applications and a cleaning step, followed by resection of the delineated area. Outcome measures were surface regression of Barrett's esophagus at 3 months, need for subsequent c-RFA, complications, and quality of resection specimens. RESULTS: 24 patients (20 men, 4 women; mean age 68 years, standard deviation [SD] 12; Barrett's esophagus median length C6M8) underwent single-session c-RFA + endoscopic resection, providing a median of 4 (interquartile range [IQR] 2 - 6) resection specimens (early cancer 18 patients; HGD 6). Complications included 1 perforation, 4 bleedings, and 5 stenoses; all were managed endoscopically. Specimens allowed assessment of neoplasia depth, differentiation, and lymphatic/vascular invasion. Median Barrett's esophagus surface regression at 3 months was 95 %. No patient required a second c-RFA procedure and 40 % required repeat endoscopic resection for visible lesions. Complete response for neoplasia was achieved in 100 % and complete response for intestinal metaplasia (CR-IM) in 95 %. CONCLUSIONS: c-RFA followed by endoscopic resection in the same session is feasible, but technically demanding and associated with a substantial rate of complications and repeat endoscopic resection. This approach should be reserved for selected cases in expert centers, with endoscopic resection and RFA 6 - 8 weeks later remaining the standard combined approach.

Learning to perform endoscopic resection of esophageal neoplasia is associated with significant complications even within a structured training program.

BACKGROUND AND STUDY AIMS: Endoscopic resection is the cornerstone of endoscopic treatment of esophageal high grade dysplasia or early cancer. Endoscopic resection is, however, a technically demanding procedure, which requires training and expertise. The aim of the current study was to prospectively evaluate efficacy and safety of the first 120 endoscopic resection procedures of early esophageal neoplasia performed by six endoscopists (20 endoscopic resections each) who were participating in an endoscopic resection training program. PATIENTS AND METHODS: The program consisted of four tri-monthly 1-day courses with lectures, live-demonstrations, hands-on training on anesthetized pigs, and one-on-one hands-on training days. Gastroenterologists from centers with multidisciplinary expertise in upper gastrointestinal oncology participated, together with an endoscopy nurse and a pathologist. Outcome measures were complete endoscopic removal of the target area and acute complications. RESULTS: A total of 120 consecutive esophageal endoscopic resection procedures (85 ER-cap, 35 multiband mucosectomy [MBM]) were performed by six endoscopists: 109 in Barrett's esophagus, 11 for squamous neoplasia; 85 piecemeal endoscopic resections (median 3 specimens, interquartile range 2 - 4 specimens). Complete endoscopic removal was achieved in 111 /120 cases (92.5 %). Six perforations occurred (5.0 %): five were effectively treated endoscopically (clips, covered stent), and one patient underwent esophagectomy. There were 11 acute mild bleedings (9.2 %), which were managed endoscopically. Perforations occurred in ER-cap procedures performed by four participants (7.1 % ER-cap vs. 0 % MBM; P = 0.18), and in 1.7 % of the first 10 endoscopic resections and 8.3 % of the second 10 endoscopic resections per endoscopist (P = 0.26). CONCLUSION: In this intense, structured training program, the first 120 esophageal endoscopic resections performed by six participants were associated with a 5.0 % perforation rate. Although perforations were adequately managed, performing 20 endoscopic resections may not be sufficient to reach the peak of the learning curve in endoscopic resection.

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study.

OBJECTIVES: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. METHODS: We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. RESULTS: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). CONCLUSIONS: In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Safety and efficacy of multiband mucosectomy in 1060 resections in Barrett's esophagus.

INTRODUCTION: Multiband mucosectomy (MBM) is a relatively new technique for endoscopic resection in Barrett's esophagus. This ligate-cut technique uses a modified variceal band ligator allowing for six consecutive resections without prior submucosal lifting. The aim was to evaluate the safety of MBM and its efficacy for complete endoscopic removal of delineated target areas in Barrett's esophagus. METHODS: Prospective registration of all MBM procedures in Barrett's esophagus was carried out between November 2004 and October 2009 in two hospitals. Prior to MBM, the target area was delineated with coagulation markings, followed by endoscopic resection until the delineated area was completely resected. Primary end points were acute (during procedure) plus early complications (<30 days) and the rate of complete endoscopic resection of the delineated target area. RESULTS: A total of 243 MBM procedures, with 1060 resections, were performed in 170 patients. MBM was performed for focal lesions (n=113), for Barrett's esophagus removal as part of a (stepwise) radical endoscopic resection protocol (n=117), and as escape treatment after radiofrequency ablation (n=13). The only acute complication was bleeding (in 3%, endoscopically managed); no perforations occurred despite absence of submucosal lifting. Early complications consisted of delayed bleeding (in 2%, endoscopically managed) and stenosis, which occurred in 48% of patients treated in a (stepwise) radical resection protocol; patients treated for focal lesions or in escape treatment showed no stenosis. Complete endoscopic resection was achieved in 91% of the focal lesions, in 86% of cases treated under the (stepwise) radical endoscopic resection protocol, and 100% for escape treatment after radiofrequency ablation. CONCLUSION: MBM is a safe and effective technique for the removal of delineated target areas in Barrett's esophagus.

Hepatic steatosis assessment with CT or MRI in patients with colorectal liver metastases after neoadjuvant chemotherapy.

PURPOSE: Preoperative radiological assessment of hepatic steatosis is recommended in patients undergoing a liver resection, but few studies investigated the diagnostic accuracy after neoadjuvant chemotherapy. The aim of this study was to compare diagnostic accuracy of preoperative CT or MRI measurements of steatosis in patients with colorectal liver metastases after induction chemotherapy. METHODS: MRI measurements (relative signal intensity decrease; RSID), N = 36, and CT scan measurements (Hounsfield units; HU), N = 32, were compared with histological steatosis assessment. Diagnostic accuracy was determined for detecting any (>5%) or marked macrovesicular steatosis (>33%). RESULTS: MRI showed the highest correlation with histology (r = 0.82, P < 0.001), compared to CT measurements (r = -0.65, P < 0.001). Based on linear regression analysis, radiological cut-off values for 5% and 33% macrovesicular steatosis, corresponded to 0.7% and 19.2% RSID in the MRI-group, and 60.4 and 54.2 HU in the CT-group, respectively. Sensitivity and specificity for the detection of any and marked macrovesicular steatosis using MRI was 87% and 69%, and 78% and 100%, respectively, and for CT, 83% and 64%, and 70% and 87%, respectively. CONCLUSION: In patients treated with neoadjuvant chemotherapy MRI measurements of steatosis showed the highest correlation coefficient and the best diagnostic accuracy, as compared to CT measurements.

Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma of the esophagus and cardia: study based on endoscopic resection specimens.

BACKGROUND: Most risk estimations for lymph node metastasis in adenocarcinoma of the esophagus and cardia (AEC) with invasion into the muscularis mucosae (m3) or submucosa are based on surgical series. This study aimed to correlate the lymph node metastasis rate with m3 and submucosal infiltration depth of AEC in endoscopic resection specimens. METHODS: Patients undergoing endoscopic resection for AEC between January 2000 and March 2008 at two centers were included if the endoscopic resection specimen showed m3 or submucosal cancer. Infiltration into the muscularis mucosae was defined as m3. Submucosal invasion was classified as sm1 (≤ 500 µm) or sm2/3 (> 500 µm). Exclusion criteria were chemotherapy or radiotherapy and nonradical endoscopic resection. RESULTS: 82 patients included 57 with m3, 12 with sm1, and 13 with sm2/3 cancers. Of the tumors, 13 were poorly differentiated and five showed lymphovascular invasion. After initial endoscopic resection, seven patients underwent surgery and 75 endoscopic therapy. No lymph node metastases were found in 158 lymph nodes of the esophagectomy specimens and none of the endoscopically treated patients were diagnosed with lymph node metastasis during a median follow-up of 26 months (interquartile range [IQR] 14 - 41). CONCLUSION: This study suggests that lymph node metastasis risk for m3 and submucosal AEC may be lower than has been assumed on the basis of surgical series, and that current guidelines are valid regarding suitability of m3 AECs for endoscopic therapy. It may also suggest that selected patients with submucosal cancers are also eligible for endoscopic management. Confirmation of these results is needed in larger series with longer follow-up.

Histological identification of epithelium in perianal fistulae: a prospective study.

AIM: A procedure often performed following fistulotomy and advancement flap is curettage of the fistula tract after fistulotomy or after closing the internal opening. Epithelialization of the fistula tract might prevent closure of the fistula tract. The aim of this study was to assess the incidence and origin of epithelialization of the fistula tract in patients with perianal fistulae undergoing fistulotomy. METHOD: Only patients with low perianal fistulae that were surgically treated by fistulotomy were included. Surgical biopsies were taken from the fistula tract from three different locations; on the proximal side at the internal opening, in the middle of the fistula tract and near the distal end close to the external opening. RESULTS: In the study period, 18 patients with low perianal fistulae were included. In 15 of the 18 patients, squamous epithelium was found at least in one of the biopsies taken from the fistula tract. Epithelium was predominantly found near the internal opening. There was no relation between the duration of fistula complaints and the amount of epithelialization (P = 0.301). The amount of epithelium was not related to the presence of a history of fistula surgery (P = 1.000). CONCLUSION: This study demonstrated epithelialization in the fistula tract in the majority of the patients surgically treated by fistulotomy for low perianal fistulae. Curettage of perianal fistulae must therefore be considered an essential step in the surgical treatment of perianal fistula.

Targets for molecular therapy in esophageal squamous cell carcinoma: an immunohistochemical analysis.

Neoadjuvant chemotherapy may improve the outcome of esophageal cancer after esophagectomy, but is accompanied by considerable toxicity by collateral destruction of normal cells. Such side effects may be avoided by developing therapies that specifically target molecular characteristics of tumors. The aim of the present study was to determine the proportion of esophageal squamous cell carcinoma (ESCC) patients that could possibly benefit from (a combination of) currently available targeted therapies, by assessing the frequency of immunohistochemical expression of their target molecular markers in ESCC tissues. Sections from a validated tissue microarray comprising 108 ESCCs were immunohistochemically stained for Bcl-2, c-KIT, cyclo-oxygenase-2 (COX-2), cyclin D1, estrogen receptor (ER), epidermal growth factor receptor (EGFR), Her-2/neu, progesterone receptor (PR), and vascular endothelial growth factor (VEGF). VEGF, cyclin D1, EGFR, and COX-2 could be detected in 55, 42, 40, and 40%, respectively. Her-2/neu, Bcl-2, and c-KIT were detected in 12, 11, and 10% of the tumors, respectively. No nuclear expression of ER or PR was noticed. Concurrent expression of two markers was noticed in 28% of ESCCs, whereas 25% of ESCCs showed concurrent expression of three markers. The concurrent expression of two of the most frequently expressed markers (VEGF, cyclin D1, EGFR, and COX-2) ranged from 11 (COX-2 and EGFR) to 26% (cyclin D1 and VEGF). The expression of all of these four markers was seen in 5% of ESCCs. Promising targets for molecular therapy in ESCC appear to be COX-2, VEGF, EGFR, and cyclin D1, as they are frequently overexpressed. Phase II clinical studies on these molecular markers may therefore be warranted. The role for targeted therapy against ER, PR, Her-2/neu, c-KIT, or Bcl-2 in ESCC seems limited.

Predicting individual survival after potentially curative esophagectomy for adenocarcinoma of the esophagus or gastroesophageal junction.

INTRODUCTION: Even after potentially curative esophagectomy, the majority of patients with adenocarcinoma of the esophagus or gastroesophageal junction die due to cancer recurrence. To predict individual disease-specific survival, a nomogram has been developed in a high-volume center in the Netherlands. The validity of this nomogram was externally tested in patients treated in another country at a different high-volume institution. METHODS: Clinicopathological data from patients who underwent a macroscopically radical resection in a high-volume center in Leuven, Belgium, were used to validate the original nomogram based on a Cox regression model. Moreover, it was examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the nomogram in the validation cohort. Calibration was evaluated by comparing the observed survival with the expected survival as predicted by the original nomogram across patients with different risk profiles. The discriminatory ability of the nomogram was determined in the validation cohort, using the concordance index and compared with the original estimate. RESULTS: A total of 382 patients were used in the validation study. The median esophageal cancer-specific survival was 38 months. None of the coefficients re-estimated in the validation cohort differed significantly from the values of the original nomogram. Observed and expected survival curves showed good calibration. Discrimination of the original nomogram was preserved in the validation cohort: the concordance index hardly decreased from 0.77 in the original cohort to 0.76 in the validation cohort. CONCLUSIONS: The nomogram model that was originally developed in a Dutch institute had good individual discriminatory properties and good overall calibration when applied to an independent series of patients. The nomogram was updated using the data from both cohorts to provide even more robust estimates of survival for individual patients. This tool is clinically helpful to supply more reliable prognostic information, to offer tailored follow-up schedules and/or novel therapeutic strategies in subgroups of patients with higher risk of recurrence.

Analysis of gene expression identifies differentially expressed genes and pathways associated with lymphatic dissemination in patients with adenocarcinoma of the esophagus.

INTRODUCTION: The presence of lymphatic dissemination is an important predictor of survival in esophageal adenocarcinoma (EA). The aim of this study was to discover a prognostic gene expression profile for lymphatic dissemination in EA and to identify genes and pathways that provide oncological insight in lymphatic dissemination. METHODS: Patients who had lymphatic dissemination (N = 55) were compared with patients without lymphatic dissemination (N = 22). Whole-genome oligonucleotide microarrays were used to evaluate the genetic signature of 77 esophageal cancers. Multiple random validation was used to analyze the stability of the molecular signature and predictive power. Gene set enrichment analysis (GSEA) was applied to elucidate oncogenetic pathways. RESULTS: Lymphatic dissemination was correctly predicted in 75 +/- 14% of lymph node positive patients. The absence of lymphatic dissemination was correctly predicted in 41 +/- 23% of lymph-node-negative patients. Argininosuccinate synthetase (ASS) was selected for validation on the protein level because it was present in most prognostic signatures as well as the list of differentially expressed genes. ASS expression was lower (P = 0.048) in patients with lymphatic dissemination than in patients without. GSEA identified that arginine metabolism pathways and lipid metabolism pathways are related to less chance of developing lymphatic dissemination. DISCUSSION: The predictive profile does not outperform current clinical practice to predict the presence of lymphatic dissemination in patients with EA. Several genes, including ASS, and genetic pathways which are important in the development of lymphatic dissemination in EA, were identified.